Drug Discovery
Several methods have been employed to find therapeutic compounds useful in the treatment of disease states. Typically, these methods involve empirical studies of organisms or cells and in some cases the components of cells to identify active therapeutic compounds which themselves, or in modified form, may have a beneficial effect on the organism or cell.
Screening methods have been used to find compounds that have a sought after-effect on a cell, i.e. the up regulation or down regulation of a gene. Screening assays are used to identify compounds and those which are identified may be used in further drug development activity. Using such methods, for example, antibodies that bind to receptors on animal tumor cells may be assayed and identified. In further drug development efforts, these antibodies or their epitopes can be analyzed and their therapeutic activity enhanced by methods known in the art.
A difficulty with such methods is that they are basically brute-force empirical methods that reveal little or nothing about the particular phenomena which take place within the cell when it is contacted with the compound identified in the screen. The actual cellular dynamics may not be understood and this may lead to development of candidate drugs deleteriously, which affect other components in the cell and cause undesirable side effects. This brute-force screening method is also limited by the speed at which assays can be conducted.
Another empirical approach used in drug development is that of screening compounds against a particular component of a cell which has been identified as being involved in a disease condition. Assays are conducted to determine the binding effect, chemical interaction or other modification of certain molecules within the cell such as genes or proteins. While the art has developed powerful, high throughput screening techniques by which tens of thousands of compounds are routinely screened for their interactive effect with one or more targets, such methodologies are still inherently empirical and leave the researcher with no fundamental information about the mechanisms of interaction of a compound identified by such methods. Thus the compound so identified may have detrimental interactions with one or more other components of a cell and may cause more harm than good. In order to determine whether the so identified compound may ultimately be useful as a therapeutic, it must be tested using in vitro studies on cells containing the particular gene or protein with which it interacts, or in vitro animal studies to determine both its beneficial and possible detrimental effects. These additional tests are extremely time-consuming and expensive.
Recently, investigators have sought to make the drug discovery process more rational by exploring the effects of a drug under development on various modifications of cells and cellular components. Friend et al., U.S. Pat. No. 6,165,709 describes methods for identifying the cellular targets of a drug by comparing (i) the effects of the drug on a wild-type cell, (ii) the effects on a wild-type cell of modifications to a putative target of the drug, and (iii) the effects of the drug on a wild-type cell which has had the putative target modified. The effect of the drug on the cell can be determined by measuring various aspects of the cell state, including gene expression, concentration of proteins, etc. While the methods described are improved over the brute-force empirical methods described above, multiple “wet” experiments must be conducted in order to determine that a gene or protein component of a cell is in fact a target of a drug and then to determine the effects of the drug on that component, on a modified component and on a wild-type cell.